Antipsychotic pharmaceutical composition

ABSTRACT

A pharmaceutical composition useful in treating psychosis contains a therapeutically effective amount of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one as an active ingredient.

FIELD OF THE INVENTION

[0001] The invention of the present application is related to a methodof using 2-[piperidinyl]methyl-2,3 -dihydroimidazo[1,2-c]quinazolin-5(6H)-one in treating psychosis in a patient.

BACKGROUND OF THE INVENTION

[0002] U.S. Pat. No. 5,158,953 discloses synthesis of a novel series of2-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones(-thiones) compounds, and they are found useful as an active ingredientfor the prophylaxis and treatment of hypertension.

[0003] U.S. Pat. No. 5,340,814 and U.S. Pat. No. 5,512,677 disclose anovel series of 3-substitutedmethyl-2,3-dihydroimidazo[1,2-c]quinazoline-5(6H)-ones (-thiones)compounds. These compounds are found useful as an active ingredient forthe treatment of hypertension and dysuria.

[0004] U.S. Pat. No. 5,932,584 discloses novel optically active3-substituted methyl-5-methylthio-2,3-dihydroimidazo [1,2-c]quinazoline(I) and 3-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one (II). These compounds are found useful as anactive ingredient for the treatment of hypertension and dysuria.

[0005] Heretofore, the series of 2-substituted or 3- substitutedmethyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (-thiones)compounds have not been found other pharmaceutical activity in additionto as an active ingredient for the treatment of hypertension anddysuria.

SUMMARY OF THE INVENTION

[0006] A primary objective of the present invention is to provide a newuse of2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one intreating psychosis in a patient.

[0007] An antipsychotic pharmaceutical composition provided according tothe present invention comprises an antipsychosis therapeuticallyeffective amount of2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-onehaving the following formula or a pharmaceutically acceptable saltthereof, as an active ingredient, in combination with a pharmaceuticallyacceptable carrier or diluent for the active ingredient:

[0008] wherein R¹ is C1-C6 alkylene, carbonyl, C1-C6 alkylene carbonylor carbonyloxy; and R² is hydrogen, C1-C6 alkyl, C1-C6 alkoxy orhalogen.

[0009] Preferably, R¹ is methylene or carbonyl, and more preferably iscarbonyl.

[0010] Preferably, R² is hydrogen or halogen, more preferably ishalogen, and most preferably is fluorine.

[0011] Preferably, the antipsychotic pharmaceutical composition of thepresent invention is administered orally.

DETAILED DESCRIPTION OF THE INVENTION

[0012] 2-[Piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones were synthesized according to the methoddisclosed in U.S. Pat. No. 5,1858,953, the details of which areincorporated herein by reference. Dopamine D_(2L) receptor binding assayand serotonin 5-HT₂ receptor binding assay were conducted to evaluatethese compounds as potential antipsychotic D_(2L)/5-HT₂ antagonists. Itis believed that a significantly greater affinity for the 5-HT₂ receptorthan for the D_(2L) receptor has the best possibility of exhibiting anatypical profile.

[0013] Two compounds having D_(2L)/5-HT₂ affinity ratios less than 1were evaluated as to their potential antipsychotic activities by testingtheir effects on apomorphine-induced climbing behavior in mice.Inhibition of climbing would suggest that a compound was a D_(2L)antagonist, a characteristic of all clinically effective antipsychotics.

[0014] Dopamine D_(2L) Receptor Binding Assay

[0015] This assay measures binding of [³H]Spiperone to human dopamineD_(2L) receptors. CHO cells stably transfected with a plasmid encodingthe human dopamine D_(2L) receptor were used to prepare membranes inmodified Tris-HCl pH 7.4 buffer. A 20 μg aliquot of membrane, in thepresence or absence of a test compound, was incubated with 0.16 nM[³H]Spiperone for 120 minutes at 25° C. Non-specific binding wasestimated in the presence of 10 μM hapoperidol. Membranes were filteredand washed three times and the filters were counted to determine[³H]Spiperone specifically bound. [References: Grandy D K, Marchionni MA, Makam H, Stofko R E, Alfano M, Frothingham L, Fischer J B,Burker-Howie K J, Bunzow J R, Server A C. Proc. Natl. Acad. Sci. (USA)86: 9762-9766, 1989; Bunzow J R, Van Tol H H, Grandy D K, Albert P,Salon J, Christie M, Machida C A, Neve K A, Civelli O. Nature 336:783-787, 1988; Hayes G, Biden T J, Selbie L A, Shine J. Mol. Endocrin.6: 920-926, 1992]

[0016] Serotonin 5-HT₂ Receptor Binding Assay

[0017] This assay measures binding of [³H]Ketanserin to serotonin 5-HT₂receptors. Whole brain (except cerebellum) membranes of male Wistarderived rats weighing 175±25 g were prepared in Tris-HCl pH 7.7 buffer.A 10 mg aliquot of membrane was incubated with 0.5 nM [³H]Ketanserin for40 minutes at 25° C. Non-specific binding was estimated in the presenceof 1 μM Ketanserin. Membranes were filtered and washed three times andthe filters were counted to determine [³H]Ketanserin specifically bound.[Reference: Leysen J E, Niemegeers C J, Van Nauten J M, Laduron D M.Mol. Pharmacol. 21: 301-314, 1982] TABLE 1 Effect of2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin- 5(6H)-onecompounds on radioligand binding assay Inhibition % Samples*Concentration D_(2L) 5-HT₂ PDC-121 30 nM 18 21 PDC-122 30 nM 13 2PDC-123 30 nM 11 4 PDC-124 30 nM 14 62 PDC-125 30 nM 23 0 PDC-126 30 nM29 11 PDC-127 30 nM 11 20 PDC-130 30 nM 16 88 PDC-131 30 nM 10 47PDC-132 30 nM 15 5

[0018]2-[4-benzyl-1-piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one

[0019] PDC-122 (Example 5 in U.S. Pat. No. 5,158,953)

[0020] 3-{2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one-2-yl}methyl-azaspiro-[5,5]undecane

[0021] PDC-123 (Example 6 in U.S. Pat. No. 5,158,953)

[0022]2-[4-piperonyl-1-piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one

[0023] PDC-124 (Example 9 in U.S. Pat. No. 5,158,953)

[0024]2-[4-Benzyl-1-piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one

[0025] PDC-126 (Example 12 in U.S. Pat. No. 5,158,953)

[0026]2-[1-benzylpiperidin-4-yl]aminomethyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one

[0027] PDC-127 (Example 11 in U.S. Pat. No. 5,158,953)

[0028]2-[4-(4-fluorobenzyl)-1-piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one

[0029] PDC-130 (Example 15 in U.S. Pat. No. 5,158,953)

[0030]2-[1-(4-p-fluorobenzoyl)piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one

[0031] PDC-131 (Example 14 in U.S. Pat. No. 5,158,953)

[0032]2-[1-(4-chlorobenzhydryl)piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one

[0033] PDC-132 (Example 16 in U.S. Pat. No. 5,158,953)

[0034] 2-[1-(4-methoxyphenyl)piperazinyl]methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one

[0035] Effects on Apomorphine-induced Climbing Behavior

[0036] Test substance was administered PO (30 mg/kg, initial dose) to agroup of 3 ICR derived male or female mice preselected non-climbinganimals weighing 22±2 gms placed in specially constructed cages.Climbing behavior was scored 0-2 for each animal from 30 to 60-minutespost-dosing: all four paws on floor=0, both forefeet holding the wall=1,all four paws on wall=2. Consequently, maximum possible group score was2×3 mice=6. A score of 3 or more (≧3) during this 30 minute observationperiod denotes dopamine-agonist activity. Mice in which no significantdopamine agonist activity occurred were then used to determineantagonistic activity. Sixty minutes after administration of testsubstance PO (30 mg/kg), apomorphine (1 mg/kg, SC) was administered andthe climbing behavior was observed and scored during the 30 minutes. Ingroups of three vehicles treated animals, this dose of apomorphineconsistently induced climbing behavior with scores of 5-6 recorded.[Reference: Psychopharmacology 50: 1-6, 1976] Percentage inhibition oftest substance on apomorphine-induced climbing behavior is calculated asfollows: ${{Inhibitation}\quad \%} = {\frac{\quad \begin{matrix}\left\lbrack {\left( {{Scores}\quad {of}\quad {apomorphine}\quad {group}} \right) -} \right. \\\left. \left( {{Scores}\quad {of}\quad {test}\quad {substance}\quad {group}} \right) \right\rbrack\end{matrix}}{\left( {{Scores}\quad {of}\quad {apomorphine}\quad {group}} \right)} \times 100\%}$

TABLE 2 Effect on apomorphine-induced climbing behavior Agonist act-Sample* Route dose ivity (score) Inhibition % Vehicle (2% Tween PO 20ml/kg 0 0 80) PDC-124 PO 30 mg/kg 0 50 PDC-130 PO 30 mg/kg 0 100 PDC-130PO 10 mg/kg 0 100 PDC-130 PO  3 mg/kg 0 60 PDC-130 PO  1 mg/kg 0 0

[0037] Although the present invention has been described with referenceto specific details of certain embodiments thereof, it is not intendedthat such details should be regarded as limitations upon the scope ofthe invention except as and to the extent that they are included in theaccompanying claims. Many modifications and variations are possible inlight of the above disclosure.

What is claimed is:
 1. An antipsychotic pharmaceutical compositioncomprising an antipsychosis therapeutically effective amount of2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-onehaving the following formula or a pharmaceutically acceptable saltthereof, as an active ingredient, in combination with a pharmaceuticallyacceptable carrier or diluent for the active ingredient:

wherein R¹ is C1-C6 alkylene, carbonyl, C1-C6 alkylene carbonyl orcarbonyloxy; and R² is hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen.2. The antipsychotic pharmaceutical composition according to claim 1,wherein R¹ is methylene or carbonyl.
 3. The antipsychotic pharmaceuticalcomposition, wherein R¹ is carbonyl.
 4. The antipsychotic pharmaceuticalcomposition according to claim 1, wherein R² is hydrogen or halogen. 5.The antipsychotic pharmaceutical composition according to claim 2,wherein R² is hydrogen or halogen.
 6. The antipsychotic pharmaceuticalcomposition according to claim 3, wherein R² is halogen.
 7. Theantipsychotic pharmaceutical composition according to claim 6, whereinR² is fluorine.
 8. The antipsychotic pharmaceutical compositionaccording to claim 6, which is orally administered.